Picosecond laser apparatus and methods for treating target tissues with same

ABSTRACT

Apparatuses and methods are disclosed for applying laser energy having desired pulse characteristics, including a sufficiently short duration and/or a sufficiently high energy for the photomechanical treatment of skin pigmentations and pigmented lesions, both naturally-occurring (e.g., birthmarks), as well as artificial (e.g., tattoos). The laser energy may be generated with an apparatus having a resonator with the capability of switching between a modelocked pulse operating mode and an amplification operating mode. The operating modes are carried out through the application of a time-dependent bias voltage, having waveforms as described herein, to an electro-optical device positioned along the optical axis of the resonator.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/721,714, filed Sep. 29, 2017, which is a continuation of U.S. patentapplication Ser. No. 14/394,960, filed Oct. 16, 2014, now U.S. Pat. No.9,780,518 issued Oct. 3, 2017, which is a national phase under 35 U.S.C.§ 371 of International Application No. PCT/US2013/032228, filed Mar. 15,2013, which claims priority to and the benefit of U.S. ProvisionalPatent Application No. 61/625,961 entitled “Picosecond Laser Apparatusand Methods for Treating Dermal Tissues with Same”, filed Apr. 18, 2012,the entire disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an apparatus and methods for deliveringlaser energy having a short pulse duration (e.g., less than about 1nanosecond) and high energy output per pulse (e.g., greater than about200 millijoules).

SUMMARY OF THE INVENTION

Disclosed herein are subnanosecond pulse duration laser systems, whichare useful for a variety of cosmetic and medical treatments. Asubnanosecond pulse duration laser apparatus includes: (a) a resonatorhaving a first mirror at one end of said resonator and a second mirrorat the opposite end of said resonator, wherein both said first mirrorand said second mirror are substantially totally reflective; and (b) alasing medium, an ultrafast switching element and a polarizing elementalong the optical axis of said resonator, wherein a first drive circuitis connected to a first end of the ultrafast switching element and asecond drive circuit is connected to a second end of the ultrafastswitching element, wherein said apparatus generates a modelocked pulseby the first circuit applying a periodic voltage waveform to the firstend of the ultrafast switching element and then amplifies the modelockedpulse by the first circuit applying a first constant voltage to thefirst end of the ultrafast switching element and maintaining aneffective reflectivity of the second mirror at substantially 100%, andthen extracts the amplified modelocked pulse by the second circuitapplying a second constant voltage to the second end of the ultrafastswitching element and maintaining an effective reflectivity of thesecond mirror at substantially 0%.

Subnanosecond pulse duration laser systems that are useful for cosmeticand medical applications provide pulsed laser energy that delivers atleast about 100 mJ/pulse and up to about 800 mJ/pulse. An exemplaryoutput energy has about 200 mJ/pulse. Likewise, such subnanosecond lasersystems have pulse durations of about 100 picoseconds to less than 1000ps, and preferably pulse durations of about 200 ps to 600 ps, or about400-500 ps.

Subnanosecond laser systems are particularly useful in the treatment ofskin and skin lesions. For example, tattoo removal requires delivery ofsubnanosecond laser pulses to the dermis, where photomechanical damageto ink particles facilitates the removal of the tattoo by the subject'simmune system. Colored tattoos or heavily shaded tattoos are easilytreated by such subnanosecond systems, using fewer treatments to achievea desired reduction in the visible appearance of the tattoo. Other skintreatments include benign pigmented lesions, where applyingsubnanosecond pulsed laser energy to benign pigmented lesions decreasesthe visible appearance of the pigmented lesions. Similar effects areseen in the treatment of vascular lesions, where applying subnanosecondpulsed laser energy to the vascular lesion thereby decreases the visibleappearance of the vascular lesions.

In addition to pigmented lesions, scars, wrinkles and striae are alsotreatable using subnanosecond pulsed laser energy. The laser energy canbe used to debulk the scars, and it creates generally areas in thetissue of microdamage from photomechanical effects. This hastissue-inductive effects, resulting in the evening-out of tissuesurfaces and the improvement in coloration and texture of the targettissue. In certain aspects of the invention, the subnanosecond pulsedlaser energy is modified with a lens, thereby producing a treatment beamhaving a nonuniform energy cross section characterized by of a pluralityof regions of relatively high energy per unit area dispersed within abackground region of relatively low energy per unit area. Such systemsoutputting subnanosecond pulse laser energy in a non-uniform beamdeliver sufficient energy to target tissue illuminated by regions ofrelatively high energy per unit area to heat the so-illuminated portionsof the target tissue to a first temperature T1 and wherein thesubstantially uniform background region of relatively low energy perunit area delivers sufficient energy to target tissue illuminated by theregions of relatively high energy per unit area to heat the soilluminated portions of the target tissue to a second temperature T2,wherein T2 is less than T1.

In other embodiments, the invention provides for wavelength shiftedsubnanosecond pulse laser, that can be frequency matched to theabsorption spectrum of a skin pigment or tattoo ink. A method forshifting the wavelength of a subnanosecond pulse laser apparatusincludes maintaining a relatively constant pulse duration by using thepulse as a pump for a laser resonator with a short roundtrip time byincluding a laser crystal with high absorption coefficient at thewavelength of the short pulse; where the round trip time of the shortlaser resonator is substantially shorter than the pumping laser pulseduration.

The invention will be more completely understood through the followingdetailed description, which should be read in conjunction with theattached drawings. Detailed embodiments of the invention are disclosedherein, however, it is to be understood that the disclosed embodimentsare merely exemplary of the invention, which may be embodied in variousforms. Therefore, specific functional details disclosed herein are notto be interpreted as limiting, but merely as a basis for the claims andas a representative basis for teaching one skilled in the art tovariously employ the invention in virtually any appropriately detailedembodiment.

DETAILED DESCRIPTION

Lasers are recognized as controllable sources of radiation that isrelatively monochromatic and coherent (i.e., has little divergence).Laser energy is applied in an ever-increasing number of areas in diversefields such as telecommunications, data storage and retrieval,entertainment, research, and many others. In the area of medicine,lasers have proven useful in surgical and cosmetic procedures where aprecise beam of high energy radiation causes localized heating andultimately the destruction of unwanted tissues. Such tissues include,for example, subretinal scar tissue that forms in age-related maculardegeneration (AMD) or the constituents of ectatic blood vessels thatconstitute vascular lesions.

Most of today's aesthetic lasers rely on heat to target tissue anddesired results must be balanced against the effects of sustained,elevated temperatures. The principle of selective photothermolysisunderlies many conventional medical laser therapies to treat diversedermatological problems such as leg veins, portwine stain birthmarks,and other ectatic vascular and pigmented lesions. The dermal andepidermal layers containing the targeted structures are exposed to laserenergy having a wavelength that is preferentially or selectivelyabsorbed in these structures. This leads to localized heating to atemperature (e.g., to about 70 degrees C.) that denatures constituentproteins or disperses pigment particles. The fluence, or energy per unitarea, used to accomplish this denaturation or dispersion is generallybased on the amount required to achieve the desired targeted tissuetemperature, before a significant portion of the absorbed laser energyis lost to diffusion. The fluence must, however, be limited to avoiddenaturing tissues surrounding the targeted area.

Fluence, however, is not the only consideration governing thesuitability of laser energy for particular applications. The pulseduration and pulse intensity, for example, can impact the degree towhich laser energy diffuses into surrounding tissues during the pulseand/or causes undesired, localized vaporization. In terms of the pulseduration of the laser energy used, conventional approaches have focusedon maintaining this value below the thermal relaxation time of thetargeted structures, in order to achieve optimum heating. For the smallvessels contained in portwine stain birthmarks, for example, thermalrelaxation times and hence the corresponding pulse durations of thetreating radiation are often on the order of hundreds of microseconds toseveral milliseconds.

Cynosure's PicoSure™ brand laser system is the first aesthetic laser toutilize picosecond technology which delivers laser energy at speedsmeasured in trillionth of seconds (10⁻¹²). PicoSure systems deliver bothheat and mechanical stress to shatter the target from within before anysubstantial thermal energy can disperse to surrounding tissue. Clinicalresults show a higher percentage of clearance achieved in fewertreatments. PicoSure systems, employing Pressure Wave™ technology, isuseful for multiple aesthetic indications such as pigmented lesions andmulti-colored tattoo removal as well as dermal rejuvenation.

An exemplary PicoSure™ brand picosecond laser apparatus is detailed inour U.S. Pat. Nos. 7,586,957 and 7,929,579, incorporated herein byreference. Such a laser apparatus provides for extremely short pulsedurations, resulting in a different approach to treating dermalconditions than traditional photothermal treatments. Laser pulses havingdurations below the acoustic transit time of a sound wave throughtargeted particles are capable of generating photomechanical effectsthrough pressure built up in the target particles. Photomechanicalprocesses can provide commercially significant opportunities,particularly in the area of treating skin pigmentations. Coupled withhigh energy output, such lasers described above are particularlysuitable for the following exemplary applications. Table 1 providesfluence values for particular spot sizes, for a subnanosecond pulselaser outputting about 200 mJ/pulse.

TABLE 1 PicoSure Fluence Spot size J/cm{circumflex over ( )}2 2 6.3692.5 4.076 3 2.831 3.5 2.080 4 1.592 4.5 1.258 5 1.019 5.5 0.842 6 0.7088 0.398 10 0.255A. Tattoo Removal

The incidence of tattoos in the U.S. and other populations, for example,continues at a significant pace. Because tattoo pigment particles ofabout 1 micron in diameter or less may be cleared from the body viaordinary immune system processes, stable tattoos are likely composed ofpigment particles having diameters on the order of 1-10 microns or more.The acoustic transit time of a sound wave in a particle of tattoopigment is calculated by dividing the radius of the particle by thespeed of sound in the particle. As the speed of sound in tattoo pigment,as well as many solid media is approximately 3000 meters/second, theacoustic transit time across such particles, and consequently the laserpulse duration required to achieve their photomechanical destruction ofthe tattoo pigment is as low as hundreds of picoseconds.

In addition to such short pulse durations, high energy laser pulses areneeded for significant disruption of tattoo pigment particles. Giventhat most tattoos are on the order of multiple centermeters in size, theideal laser for tattoo removal should ideally employ a beam having arelatively large spot size. Fluences of several joules per squarecentimeter and treatment spot sizes of a few millimeters in diametertranslate to a desired laser output with several hundred millijoules(mJ) per pulse or more, and are suitable for tattoo removal.

An exemplary sub-nanosecond tattoo removal laser apparatus as describedin our U.S. Pat. Nos. 7,586,957 and 7,929,579 and as described herein isused to generate pulsed laser energy having a subnanosecond pulseduration of about 100-950 picoseconds, preferably with an energydelivery of about 200-750 mJ/pulse. Such exemplary subnanosecond laserapparatus includes a resonator with two substantially totally reflectivemirrors at opposite ends of its optical axis. An alexandrite crystallasing medium, a polarizer, and a Pockets cell are positioned along thisoptical axis. An optical flashlamp is also included for pumping thealexandrite lasing medium, which generates laser energy having awavelength in the range of about 700-950 nm.

The pulsed laser energy described above is generated by pumping thelasing medium and first establishing a modelocked pulse oscillating inthe resonator. In the modelocked pulse operating mode, a time-dependentvoltage waveform, as described herein, is applied to the Pockets cell.This waveform results from the sum of a constant baseline voltage and atime-dependent differential voltage. The baseline voltage is in therange of 1000-1500 volts (representing 40%-60% of the Pockets cellquarter wave voltage, or 2500 volts) and is negatively offset ormodulated by the time-dependent differential voltage, having anamplitude in the range of 250-750 volts (representing 10%-30% of thePockets cell quarter wave voltage). The period of the resulting voltagewaveform is in the range from 5-10 ns and is equal to the round triptime of the oscillating laser energy in the resonator. The voltageapplied to the Pockels cell is thus modulated at a frequency in therange from 100-200 MHz.

Subsequently, the modelocked pulse established as described above isamplified by discharging the Pockels cell to essentially 0 volts.Oscillating laser energy is reflected between the mirrors at each end ofthe resonator, with essentially no losses. This laser energy thereforerapidly increases in amplitude by extracting energy previously pumpedand stored in the alexandrite crystal during modelocking. When the laserenergy has reached the desired energy level as indicated above, it isextracted from the resonator by applying the quarter wave voltage of2500 volts to the Pockels cell.

The switching electronics used to operate the laser in modelocked pulseand amplification modes, and finally to extract the amplified pulse asdiscussed above, comprise five MOFSET switches, two high speed diodes,and three voltage sources having voltages V1 in the range of +1000 to+1500 volts, V2 in the range of +250 to +750 volts, and V3 in the rangeof −1000 to −1500 volts. The switches, diodes, and voltage sources areconfigured as shown above.

Laser energy having the pulse duration and energy as described isapplied to a patient undergoing treatment for the removal of a tattoo.This laser energy is applied over the course of a 30-minute treatmentsession to all areas of the skin having undesired tattoo pigmentparticles. Photomechanical disruption of these particles is effectedusing the short pulse duration (below the transit time of a sound wavethrough the targeted tattoo pigment particles), together with a fluencein the range of 2-4 J/cm². This fluence is achieved in the above devicewith a laser energy spot diameter of about 5 mm.

Most if not all of the undesired tattoo pigment particles Areeffectively photomechanically disrupted, destabilized, and/or brokenapart using one or two treatments. As a result, the disrupted particlesare cleared from the body via normal physiological processes, such asthe immune response. The tattoo is thus eventually cleared from the skinwith no remaining visible signs. Such subnanosecond laser devices areparticularly well suited for removal of tattoos having colored inks,colors being far more recalcitrant to treatment with traditional lasertreatments than black inks. Likewise, tattoos having heavy coloration orshading are more amenable to treatment using subnanosecond lasersystems. Similarly, subnanosecond lasers provide for tattoo removal withfewer treatments than compared to traditional laser systems.

B. Benign Pigmented Lesions

Numerous types of benign pigmented lesions of the skin, connectivetissue, mucosal tissue and vasculature are treatable using thesubnanosecond laser systems described herein.

Nevi are a broad category of generally well circumscribed and chroniclesions of the skin that can be congenital or develop later in life.Vascular nevi such as hemangioma, are derived from structures of theblood vessels. Epidermal nevi such as seborrheic keratoses are derivedfrom keratinocytes. Connective tissue nevi are derived from connectivetissues. Melanocytic nevi such as nevomelanocytic nevi are pigmentedlesions that morphologically can be flat macules or raised papules, andare characterized by clusters of melanocytes. In addition to the above,dermal melanocytoma (blue nevi), acral nevi, nevus spilus (also known asspeckled lentiginous nevus), nevus of Ota/Ito and Becker's nevus are allexemplary and non-limiting nevi that are suitable for treatment usingthe above laser apparatus.

Lentigines are similarly treatable. These are pigmented spots on theskin typically small and with a clearly-defined edge, surrounded bynormal-appearing skin. These are benign melanocytic hyperplasias thatare linear rather than raised, with the melanocytes generally restrictedto the cell layer directly above the basement membrane of the epidermis.Lentigines also appear in mucosal tissues. Lentigines are distinguishedfrom ephelids (freckles) based on melanocyte proliferation, wherelentigines display an increased number of melanocytes but ephelids havenormal numbers of melanocytes that overexpress melanin.

Other forms of congenital dermal pigmentation are equally suitable totreatment using the above laser apparatus, usually being larger areasrequiring larger laser spot sizes. For example, café au lait macules,congenital dermal melanocytosis, and dermal melanocytosis are allexemplary types of benign, flat, pigmented birthmarks, generally withwavy borders and irregular shapes. Other exemplary pigmented lesionsdevelop as one ages, or due to hormonal changes, infection or treatmentwith pharmaceutical agents. For example, melasma a/k/a chloasma faciei(colloquially “the mask of pregnancy”) is a tan or dark skindiscoloration. Postinflammatory hyperpigmentation (also known aspostinflammatory hypermelanosis) can result from natural or iatrogenicinflammatory conditions, and are commonly caused by increased epidermalpigmentation. This can occur through increased melanocyte activity or bydermal melanosis from melanocyte damage with melanin migration from theepidermis into the dermis. Drug-induced pigmentation of the skin mayoccur as a consequence of drug administration, related to deposition ofthe drug in the tissues. Minocycline is known for this effect. Pigmentedlesions aren't confined to the dermal tissues. Ochronosis is a pigmentedlesion caused by the accumulation of homogentisic acid in connectivetissues. In addition, melanonychia is aberrant pigmentation of thenormal nail plate. These exemplary conditions are all suitable totreatments using the above described laser systems.

To treat the above conditions, it is generally accepted that destructionof melanosomes is pulse-width-dependent. Using traditional lasersystems, pulse durations of between 40 nanoseconds and 750 nanosecondshave been shown to be effective, but longer pulse durations (eg, 400microseconds) do not appreciably damage the melanosomes, Likewise,Q-switched Nd:YAG laser systems have shown immediate skin whitening withthreshold energy exposures generating fluence values of 0.11, 0.2, and 1mJ/cm² respectively at 355, 532, and 1064 nm wavelengths.

Melanin has a broad absorption spectrum, and lasers emitting atwavelengths of about 500-1100 nm provide for good skin penetration andselective melanosome absorption without undue hemoglobin absorption.Exemplary lasers include 510-nm pulsed dye, 532-nm frequency-doubledNd:YAG, 694-nm ruby, 755-mn alexaridrite, and near-infrared Nd:YAGlasers emitting at 1064 nm. Other lasers have been used successfully totreat pigmented lesions, including argon, krypton, copper, carbondioxide, and Er:YAG lasers, but with these systems there is a trade-offbetween pigment destruction and collateral damage to other chromophoresand tissues.

An exemplary subnanosecond laser system for treating pigmented lesionsis described by the above apparatus generating pulsed laser energyhaving a pulse duration of about 100-950 picoseconds with an energyoutput of about 200-750 mJ/pulse. Laser energy having a wavelength inthe range of 700-950 nm provides excellent specificity for melanin.Photomechanical disruption is effected using the short pulse duration(below the transit time of a sound wave through the targeted pigmentparticles), together with a fluence in the range of 2-4 J/cm². Thisfluence is achieved with a laser energy spot diameter of about 5 mm,which can be changed according to the area of the target. Treatmenttimes will vary with the degree of pigmentation and the shapes of thetargets. In addition to decreasing the visible appearance of pigmentedlesions, photomechanical microdamage to target tissues caused bysubnanosecond pulses promotes a healing response that can decrease thesize and shape of the lesion.

C. Vascular Lesions

Vascular lesions refer to a broad category of pigmented malformations,generally congenital, that are due to localized defects of vascularmorphogenesis. These include capillary, venous, arteriovenous, andlymphatic malformations as well as lesions involving only the skin andsubcutaneous tissues. Exemplary non-limiting examples include capillaryvascular malformation, telangiectasis, cherry angioma, angiofibroma,dyschromia, port wine stain birthmarks, strawberry hemangiomas, rosacea,pyogenic granuloma and other vascular malformations.

The targeted chromophore for vascular lesions is intravascularoxyhemoglobin, with maximal light absorption occurring in the range ofyellow and green light, i.e., at 418, 542, and 577 nm and in thenear-infrared spectrum. Traditional approaches to treating vascularlesions involved pulsed dye lasers, typically operating at wavelengthssuch as 585-nm or 595-nm, frequency-doubled Nd:YAG lasers at wavelengthsof 532 nm, and infrared lasers such as alexandrite or diode lasershaving wavelengths of 1064 nm. Histologically, the targets of treatmentare postcapillary venules, capillaries, or arterioles, generally atdepths range from 200 to 300 μm. Accordingly, a deeper penetration ofthe laser beam is desirable, particularly where heating of the surfaceskin can lead to excessive scarring. Typical treatment parametersinvolve fluences of 8 to 10 J/cm², and a 5-10 mm spot size.

An exemplary system to treat vascular lesions is described by anapparatus generating pulsed laser energy having a pulse duration ofabout 100-950 ps with energies of about 200-750 mJ/pulse. Laser energyhaving a wavelength in the range of 500-600 nm provides excellentspecificity for oxyhemoglobin. Photomechanical disruption is effectedusing the short pulse duration (below the transit time of a sound wavethrough the targeted pigment particles), together with a fluence in therange of 7-10 j/cm². This fluence is achieved with a laser energy spotdiameter of about 5 mm, which can be changed according to the area ofthe target. Treatment times will vary with the degree of pigmentationand the shapes of the targets.

D. Scar Tissue

Various types of scarring are treatable using lasers. Exemplarynon-limiting types include hypertrophic scars, keloids and atrophicscars. Hypertrophic scars are cutaneous deposits of excessive amounts ofcollagen. These give rise to a raised scar, and are commonly seen atprior injury sites particularly where the trauma involves deep layers ofthe derrnis, i.e., cuts and bums, body piercings, or from pimples.Hypertrophic scars commonly contain nerve endings are vascularized, andusually do not extend far beyond the boundary of the original injurysite.

Similarly, a keloid is a type of scar resulting from injury, that iscomposed mainly of either type III or type I collagen. Keloids resultfrom an overgrowth of collagen at the site of an injury (type III),which is eventually replaced with type 1 collagen, resulting in raised,puffy appearing firm, rubbery lesions or shiny, fibrous nodules, whichcan affect movement of the skin. Coloration can vary from pink to darkerbrown.

Atrophic scarring generally refers to depressions in the tissue, such asthose seen resulting from Acne vulgaris infection. These “ice pick”scars can also be caused by atrophia maculosa varioliformis cutis(AMVC), which is a rare condition involving spontaneous depressedscarring, on the cheeps, temple area and forehead.

Laser treatments are suitable for hypertrophic and atrophic scars, andkeloids, and common approaches have employed pulsed dye lasers in suchtreatments. In raised scars, this type of therapy appears to decreasescar tissue volume through suppression of fibroblast proliferation andcollagen expression, as well as induction of apoptotic mechanisms.Combination treatment with corticosteroids and cytotoxic agents such asfluorouracil can also improve outcome. In atrophic scars, treatments caneven out tissue depths.

Striae (stretch marks) are a form of scarring caused by tearing of thedermis. They result from excess levels of glucocorticoid hormones, whichprevent dermal fibroblasts from expressing collagen and elastin. Thisleads to dermal and epidermal tearing. Generally, 585-nm pulsed dyelaser treatments show subjective improvement, but can increasepigmentation in darker skinned individuals with repeated treatments.Fractional laser resurfacing using scattered pulses of light has beenattempted. This targets small regions of the scar at one time, requiringseveral treatments. The mechanism is believed to be the creation ofmicroscopic trauma to the scar, which results in new collagen formationand epithelial regeneration. Similar results can be achieved, albeit tothe total scar, through the use of modified laser beams as described inour U.S. Pat. No. 7,856,985, detailing the use of non-uniform beamradiation to create within the beam area, discrete microtrauma sitesagainst a background of tissue inducing laser radiation.

An exemplary system for treating scars is described by the aboveapparatus generating pulsed laser energy having a pulse duration ofabout 100-950 ps with energies of about 200-750 mJ/pulse. Laser energyhaving a wavelength in the range of 500-1100 nm provides excellentspecificity for collagen. Photomechanical disruption of the scar tissueis effected using the short pulse duration (below the transit time of asound wave through the targeted tissue), together with a fluence in therange of 2-4 J/cm². This fluence is achieved with a laser energy spotdiameter of about 5 mm, which can be changed according to the area ofthe target. Treatment times wilt vary with the degree of scarring andthe shapes of the targets. The photomicrodamage from subnanosecondpulses can debulk the scar, resolve coloration differences between itand healthy tissues, and promotes tissue healing responses which havethe effect of softening the scar. Modifying the output beam as describedin U.S. Pat. No. 7,856,985 provides a particularly useful approach toreducing scar appearance and inducing epithelial restoration within thescar.

E. Dermal Rejuvenation

A non-uniform output beam is delivered to tissue from a source of lightas described in our patent applications U.S. Ser. Nos. 11/347,672;12/635,295; 12/947,310, and PCT/US10/026432. The non-uniform beam ischaracterized by a cross-section corresponding to an array of relativelysmall, relatively high-intensity, spaced-apart central regionssuperimposed on a relatively large, and relatively low-intensitybackground region. Operatively, this produces within the area of thebeam, relatively hotter regions and relatively cooler regions. Thisnon-uniform beam provides for unique physiological effects as comparedto standard uniform output laser beams that demonstrate relative uniformenergy output across the planar surface of the beam. Such effects arerelated to the fluence and duration of the light pulse, and includevarious quantifiable physiological effects. Exemplary temperaturedependent effects include but are not limited to parakeratosis,perivascular mononuclear infiltration, keratinocyte necrosis, collagendenaturation, and procollagen expression in dermal cells. Other cellularmarkers (e.g., nucleic acids and proteins) are useful in detecting moresubtle responses of skin to less aggressive treatments.

Various combinations of wavelength, power, spot size, treatment durationand recovery intervals are possible, and the particular combination isselected based on the desired therapeutic effect. For example, intreating age spots and pigmentation a device wavelength is chosen to bepreferentially absorbed by melanin (between 400 nm and 1400 nm, and morepreferably 500 nm to 1100 nm). Accordingly, an exemplary device for suchpurposes has a wavelength of about 750 nm, a pulse duration of about 500to 900 ps and an overall treatment area of 1 cm² that is output as anon-uniform beam characterized by a cross-section corresponding to anarray of relatively small, relatively high intensity, spaced-apartcentral regions superimposed on a relatively large, relatively lowintensity background region. If such exemplary device has about 0.2 J ofenergy delivered into the treatment area, or about 0.2 J/cm² averagefluence. Using a lens that renders the output beam non-uniform,delivering relatively high intensity spaced-apart central regions at 1mm center-to-center distances surrounded by low intensity backgroundregions, in such device, there are about 115 discrete subzones (e.g.,combined areas of relatively high and relatively low intensity) persquare centimeter in that arrangement, which results in about 1.73 mJdelivered to each subzone. Within each subzone, if the high intensityspaced-apart central region is about 120 μm in diameter andapproximately 80% of the energy is delivered into the high intensityspaced-apart central regions, then the fluence within each highintensity region is approximately 12.2 J/cm². That fluence value in thedevice is comparable to the treatment fluence delivered by high-poweredAlexandrite uniform spot lasers having pulse durations of about 50 ns,which are the systems commonly used to treat uneven skin pigmentation inclinical settings by medically trained professionals. Unlikeuniform-beam devices, using the non-uniform beam technology for anyindividual treatment session, only a relatively small percentage of theirradiated skin surface is actually treated with high intensity light,and thereby only a subpopulation of melanocytes receive a cellulardisruptive dose of thermal energy, leading to a relatively smallerpercentage of melanocyte damage per treatment area compared to uniformbeam treatments. This advantageously reduces any sharp boundariesbetween treated and untreated skin, thereby reducing the need forspecial operator skills and techniques.

Good cosmetic effects can be produced by such non-uniform irradiation oftissues, due to differential effects occurring in both the relativelyhigh intensity spaced-apart central regions of the beam and in therelatively low intensity background region. By way of illustration,within the spaced-apart central regions it is possible to causerelatively localized heating of tissues therein to a temperature T1sufficient to heat up the melanocytes to a temperature sufficient todisrupt cellular processes (e.g., about 45 degrees C. or higher), impairtheir function and decrease their pigment output. Simultaneously duringthe treatment, within the low intensity background regions at a lowerrelative temperature T2 (e.g., less than 45 degrees C. to about 35degrees C.), cellular growth and collagen production is induced withoutcausing undesirable thermal effects to the treated tissue within thelower energy regions. The result of such treatment is an improvement toboth skin texture and coloration. Other differential effects on tissuescan be realized as well. By way of further example, temperatures atabout 70 degrees C. can serve to denature collagen, so within thespaced-apart central regions it is possible to cause relativelylocalized heating of tissues therein to a temperature T1 sufficient toremodel collagen structures, while simultaneously within the lowintensity background regions at a lower relative temperature T2,collagen production is induced without causing undesirable thermaleffects to the treated tissue within the background regions.

Likewise, by decreasing the amount of energy delivered by the beam it ispossible to select for specific thermal effects on tissues. For example,in our U.S. Pat. No. 7,856,985 we disclose collagen remodeling attemperatures where T1 is approximately 70 degrees C. or greater whilethe irradiated tissues in the cooler regions of the beam (e.g., attemperature T2) are not substantially adversely affected. The deviceused generating a non-uniform beam output, permits more selectiveapplication with less collateral tissue damage. However, for reducingage spots and evening skin pigmentation, melanocyte cell membrane damagewith consequent cellular disruption is achieved at lower T1 temperaturesof approximately 45-50 degrees C. (unless such heating is quitetransient). Higher temperatures are suitable, and cause permanentdisruption of melanocytes, but above 50 degrees C. more extensivethermal effects are seen in the tissue, that must be evaluated againsttherapeutic benefits. Below the temperature threshold for causingcellular damage and disruption, positive effects on skin tone are seen.At a T1 temperature of less than about 50 degrees C., cells are notsubstantially damaged but are still induced to generate a healingresponse and express elastin, procollagen, keratin and other markers fordermal rejuvenation. So a device generating regions capable of elevatingtissue temperatures to a T1 of about 45 degrees C. against a backgroundT2 of about 37 degrees.

The overall effect of treatments on skin tone, wrinkling andpigmentation provide the best indication of therapeutic efficacy, butsuch treatments also leave histological evidence that can be discerned.At higher energies, thermal damage is easy to detect. For more moderateenergies, microthermal damage can produce effects that are seen withmagnification although erythema provides a good marker for microthermalinjury and it does not require microscopic examination of tissues fromthe treatment site. Generally, in the absence of any visually observableerythema, the cellular effects will be more subtle, or may take longerto manifest themselves or may require multiple treatments before visualimprovement of the skin is seen. At lower output energies, shorter pulsedurations, and longer intervals between treatments, it is advantageousto use more sensitive techniques to assay for cellular changes. Certaintechniques provide for quantitative analysis, which are correlated todescribe a dose-response relationship for the non-uniform beam, as it isused in dermal rejuvenation applications. Such techniques include butare not limited to RT-PCR and/or real-time PCR, either of which permitsquantitative measurements of gene transcription, useful to determine howexpression of a particular marker gene in the treated tissues changesover time. In addition to nucleic acid-based techniques, quantitativeproteomics can determine the relative protein abundance between samples.Such techniques include 2-D electrophoresis, and mass spectroscopy (MS)such as MALDI-MS/MS and ESI-MS/MS. Current MS methods include but arenot limited to: isotope-coded affinity tags (ICAT); isobaric labeling;tandem mass tags (TMT); isobaric tags for relative and absolutequantitation (iTRAQ); and metal-coded tags (MeCATs). MeCAT can be usedin combination with element mass spectrometry ICP-MS allowing first-timeabsolute quantification of the metal bound by MeCAT reagent to a proteinor biomolecule, enabling detection of the absolute amount of proteindown to attomolar range.

An exemplary system for dermal rejuvenation is described by the aboveapparatus generating pulsed laser energy having a pulse duration ofabout 100-950 ps with energies about 200-750 mJ/pulse. Laser energyhaving a wavelength in the range of 500-1100 nm provides excellentspecificity for collagen. Photomechanical disruption of the targettissue is effected using the short pulse duration (below the transittime of a sound wave through the targeted tissue), together with afluence in the range of 2-4 J/cm². This fluence is achieved with a laserenergy spot diameter of about 5 mm, which can be changed according tothe area of the target. Treatment times will vary according to thedesired effects. Modifying the output beam as described in U.S. Pat. No.7,856,985 provides a particularly useful approach to rejuvenating tissueand inducing collagen and epithelial cell restoration within the tissue.

F. Frequency Shifting

The subnanosecond laser systems may include a frequency shiftingapparatus, which can be matched to the absorbtion spectrum of endogenousskin pigmentation or exogenous tattoo pigments to be targeted. Such asystem comprises a rare earth doped laser gain crystal for exampleNd:YVO4, and a frequency doubling crystal for example KTP. Rare earthdoped laser crystals that generate a polarized laser beam like Nd:YVO4are preferred. Crystals like Nd:YAG or Nd doped glasses can be used withan additional polarizing element in the resonator. The input side of theNd:YVO4 crystal is AR coated for the alexandrite wavelength and HRcoated for 1064 nm. The output side of the crystal is HR coated for thealexandrite wavelength and has approximately 20 to 70% reflectivity at1064 nm. The Nd:YVO4 crystal length is chosen so that it absorbs most(greater than 90%) of the alexandrite laser pulse in the two passesthrough the crystal. For Nd doping in the range 1 to 3% the Nd:YVO4crystal can be chosen to be around 3 mm long. There are no other opticalelements in the resonator and the resonator length is equal to thecrystal length 3 mm. That means the resonator round-trip time is around36 ps—this is substantially less than the pulse duration of thealexandrite pumping pulse (around 500 to 800 ps). The 1064 nm pulsegenerated in the very short round trip time Nd:YVO4 resonator will beslightly longer than the pumping alexandrite pulse and it will beshorter than 1000 ps. The quantum defect will account for a 30% pulseenergy loss and another 15% of the energy is likely to be lost due tocoatings, crystal and geometry imperfection for an overall energyconversion efficiency of around 50 to 60%. That means a 100 mJ pulseenergy can be expected at 1064 nm. Conservatively it is estimated thatthe second harmonic conversion in the KTP crystal will be around 50% anda 50 mJ pulse energy can be expected at 532 nm. The red tattoo pigmentshave high absorption at 532 nm. A 50 mJ 532 nm pulse with a pulseduration less than 1000 ps is expected to be effective at disrupting redtattoo granules.

When the Nd:YAG crystal or Nd doped glasses are used in the shortresonator an extra polarizing element has to be used to generate apolarized 1064 nm pulse. The cross-section depicts a short Nd:YAGresonator consisting of two identically shaped crystals with one facecut at an angle that is AR coated for the alexandrite wavelength andpolarized coating for 1064 nm (high p transmission). The flat faces ofthe two Nd:YAG crystals have different coatings—one is AR coated at 755nm and FIR coated at 1064 nm and the other is HR coated for 755 nm andhas an output coupler reflectivity around 50 to 80% for 1064 nm. Thehigher output coupler reflectivity for the Nd:YAG crystal compared tothe Nd:YVO4 crystal is due to the lower gain cross-section in Nd:YAG.

Generating a short 1064 nm pulse depends on two factors. One is thepulse duration of the pumping alexandrite pulse. Shorter pumping pulseswill lead to shorter generated pulses at 1064 nm. The second factor isthe 1064 nm resonator round trip time that is determined by the lengthof the Nd doped crystal. Shorter crystals lead to shorter roundtriptime, however the crystal has to be sufficiently long to absorb greaterthan 90% of the alexandrite energy. For example, an 8 mm long Nd:YAGresonator would have a 97 ps round trip time. That round trip time islonger than the round trip time that can be achieved with a Nd:YVO4resonator, but still it is much shorter than the pumping Alexandritelaser pulse duration. One possible way to shorten the crystal length isto tune the alexandrite laser in the range 750 to 760 nm for maximumabsorption in the Nd doped crystal and use the minimum possible crystallength. In addition, tuning the atexandrite laser in the range 750 to757 nm allows for the alexandrite wavelength to be set to avoid theexcited state absorption bands in the Nd ion as described by Kliewer andPowell, IEEE Journal of Quantum Electronics vol. 25, page 1850-1854,1989.

The invention claimed is:
 1. A method of treating a target tissuecomprising: generating, using a laser source, an output beam having asubnanosecond pulse duration; modifying the output beam, using anoptical system, to provide a photomechanically disruptive treatmentbeam; directing the photomechanically disruptive treatment beam to oneor more regions of the target tissue; photomechanically disrupting theone or more regions of the target tissue; and inducing collagenrestoration within the target tissue in response to photomechanicallydisrupting the one or more regions of target tissue.
 2. The method ofclaim 1 further comprising rejuvenating the target tissue.
 3. The methodof claim 2 wherein rejuvenating the target tissue comprises inducingepithelial cell restoration within the target tissue in response tophotomechanically disrupting the one or more regions of the targettissue.
 4. The method of claim 2 wherein rejuvenating the target tissuecomprises increasing amount of collagen disposed therein relative tountreated tissue.
 5. The method of claim 1 wherein the photomechanicallydisruptive treatment beam has a non-uniform beam profile, thenon-uniform beam profile comprising a plurality of regions of relativelyhigh energy per unit area dispersed within a substantially uniformbackground region of relatively low energy per unit area.
 6. The methodof claim 5 further comprising increasing temperature of a first regionof target tissue to a first temperature T1 and increasing or maintainingtemperature of a second region of target tissue to a second temperatureT2 in response to distribution of regions of relatively high energy andregions of relatively low energy.
 7. The method of claim 6 wherein T1ranges from about 45 degrees Celsius to about 50 degrees Celsius.
 8. Themethod of claim 6 wherein T1 is approximately 70 degrees Celsius orgreater.
 9. The method of claim 1, wherein the photomechanicallydisruptive treatment beam has an energy spot diameter of about 5 mm. 10.The method of claim 1, wherein the photomechanically disruptivetreatment beam has an energy spot diameter which can be changedaccording to area of the target tissue.
 11. A method of treating atarget tissue comprising one or more pigments, the method comprising:generating, using a laser source, an output beam having a subnanosecondpulse duration; modifying the output beam, using an optical system, toprovide a photomechanically disruptive treatment beam; directing thephotomechanically disruptive treatment beam to one or more pigments ofthe target tissue, wherein the one or more pigments are visible prior totreatment; and decreasing visible appearance of one or more pigmentswithin the target tissue in response to the photomechanically disruptivetreatment beam.
 12. The method of claim 11, wherein the one or morepigments comprise one or more tattoo pigments.
 13. The method of claim11, wherein the target tissue is a pigmented lesion.
 14. The method ofclaim 11 wherein the one or more pigments is melanin.
 15. The method ofclaim 11 wherein decreasing visible appearance of one or more pigmentscomprises decreasing visible appearance of a pigmented lesion within thetarget tissue.
 16. The method of claim 11, wherein the photomechanicallydisruptive treatment beam has a non-uniform beam profile, thenon-uniform beam profile comprising a plurality of regions of relativelyhigh energy per unit area dispersed within a substantially uniformbackground region of relatively low energy per unit area.
 17. The methodof claim 16 further comprising increasing temperature of a first regionof target tissue to a first temperature T1 and increasing or maintainingtemperature of a second region of target tissue to a second temperatureT2 in response to distribution of regions of relatively high energy andregions of relatively low energy.
 18. A method of treating tissuecomprising oxyhemoglobin, the method comprising: generating, using alaser source, an output beam having a subnanosecond pulse duration;modifying the output beam, using an optical system, to provide aphotomechanically disruptive treatment beam; directing thephotomechanically disruptive treatment beam to one or more regions ofthe target tissue comprising oxyhemoglobin, wherein the target tissuecomprises a vascular lesion that is visible prior to treatment; anddecreasing visible appearance of the vascular lesion in response to thephotomechanically disruptive treatment beam.
 19. The method of claim 18,wherein the photomechanically disruptive treatment beam has anon-uniform beam profile, the non-uniform beam profile comprising aplurality of regions of relatively high energy per unit area dispersedwithin a substantially uniform background region of relatively lowenergy per unit area.
 20. The method of claim 19 further comprisingincreasing temperature of a first region of target tissue to a firsttemperature T1 and increasing or maintaining temperature of a secondregion of target tissue to a second temperature T2 in response todistribution of regions of relatively high energy and regions ofrelatively low energy.
 21. The method of claim 18, wherein thephotomechanically disruptive treatment beam has an energy spot diameterof about 5 mm.
 22. The method of claim 18, wherein the photomechanicallydisruptive treatment beam has an energy spot diameter which can bechanged according to area of the target tissue.